Skip to main content
Log in

Cognitive enhancing effects of ghrelin receptor agonists

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor, has been shown to play a role in multiple physiological processes including appetite regulation, metabolism and, more recently, dendritic spine architecture, long-term potentiation and cognition.

Objective

The objective of this study was to determine the effects of two structurally non-peptide ghrelin receptor agonists (GSK894490A and CP-464709-18) on rodent cognition.

Methods

All experiments were performed in male Lister hooded rats. Effects of the test compounds on rat cognitive performance was determined using the novel object recognition test, a modified water maze paradigm and a scopolamine-induced deficit in cued fear conditioning. These tests were chosen as they each probe a relatively independent cognitive domain and therefore potentially have differing underlying neural substrates.

Results

Both compounds significantly improved performance in the novel object recognition and modified water maze tests but were unable to attenuate a scopolamine deficit in cued fear conditioning.

Conclusions

These results demonstrate that the small-molecule ghrelin receptor agonists profiled here readily cross the blood/brain barrier and elicit pro-cognitive effects in recognition and spatial learning and memory tests. Based on these observations, the central ghrelin receptor would appear to be a chemically tractable receptor and perhaps should be considered as a new drug target for therapeutic approaches to treat diseases affecting cognition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Fujimiya M, Katsuura G, Makino S, Fujino MA, Kasuga M (2001) A role of ghrelin in neuroendocrine and behavioral responses to stress in mice. Neuroendocrinology 74:143–147

    Article  PubMed  CAS  Google Scholar 

  • Binn M, Albert C, Gougeon A, Maerki H, Coulie B, Lemoyne M, Rabasa Lhoret R, Tomasetto C, Poitras P (2006) Ghrelin gastrokinetic action in patients with neurogenic gastroparesis. Peptides 27:1603–1606

    Article  PubMed  CAS  Google Scholar 

  • Bowers CY (1998) Growth hormone-releasing peptide (GHRP). Cell Mol Life Sci 54:1316–1329

    Article  PubMed  CAS  Google Scholar 

  • Broglio F, Gottero C, Arvat E, Ghigo E (2003) Endocrine and non-endocrine actions of ghrelin. Horm Res 59:109–117

    Article  PubMed  CAS  Google Scholar 

  • Buresova O, Krekule I, Zahalka A, Bures J (1985) On-demand platform improves accuracy of the Morris water maze procedure. J Neurosci Methods 15:63–72

    Article  PubMed  CAS  Google Scholar 

  • Camina JP (2006) Cell biology of the ghrelin receptor. J Neuroendocrinol 18:65–76

    Article  PubMed  CAS  Google Scholar 

  • Cao JM, Ong H, Chen C (2006) Effects of ghrelin and synthetic GH secretagogues on the cardiovascular system. Trends Endocrinol Metab 17:13–18

    Article  PubMed  CAS  Google Scholar 

  • Carlini VP, Varas MM, Cragnolini AB, Schioth HB, Scimonelli TN, de Barioglio SR (2004) Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin. Biochem Biophys Res Commun 313:635–641

    Article  PubMed  CAS  Google Scholar 

  • Carlini VP, Martini AC, Schioth HB, Ruiz RD, Fiol de Cuneo M, de Barioglio SR (2008) Decreased memory for novel object recognition in chronically food-restricted mice is reversed by acute ghrelin administration. Neuroscience 153:929–934

    Article  PubMed  CAS  Google Scholar 

  • Carlini VP, Monzon ME, Varas MM, Cragnolini AB, Schioth HB, Scimonelli TN, de Barioglio SR (2002) Ghrelin increases anxiety-like behavior and memory retention in rats. Biochem Biophys Res Commun 299:739–743

    Article  PubMed  CAS  Google Scholar 

  • Carpino PA, Lefker BA, Toler SM, Pan LC, Hadcock JR, Murray MC, Cook ER, DiBrino JN, DeNinno SL, Chidsey-Frink KL, Hada WA, Inthavongsay J, Lewis SK, Mangano FM, Mullins MA, Nickerson DF, Ng O, Pirie CM, Ragan JA, Rose CR, Tess DA, Wright AS, Yu L, Zawistoski MP, Pettersen JC, DaSilva-Jardine PA, Wilson TC, Thompson DD (2002) Discovery and biological characterization of capromorelin analogues with extended half-lives. Bioorg Med Chem Lett 12:3279–3282

    Article  PubMed  CAS  Google Scholar 

  • Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML, Garcia-Segura LM, Nillni EA, Mendez P, Low MJ, Sotonyi P, Friedman JM, Liu H, Pinto S, Colmers WF, Cone RD, Horvath TL (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37:649–661

    Article  PubMed  CAS  Google Scholar 

  • Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, Gaskin FS, Nonaka N, Jaeger LB, Banks WA, Morley JE, Pinto S, Sherwin RS, Xu L, Yamada KA, Sleeman MW, Tschop MH, Horvath TL (2006) Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci 9:381–388

    Article  PubMed  CAS  Google Scholar 

  • Dornonville de la Cour C, Bjorkqvist M, Sandvik AK, Bakke I, Zhao CM, Chen D, Hakanson R (2001) A-like cells in the rat stomach contain ghrelin and do not operate under gastrin control. Regul Pept 99:141–150

    Article  PubMed  CAS  Google Scholar 

  • Enomoto M, Nagaya N, Uematsu M, Okumura H, Nakagawa E, Ono F, Hosoda H, Oya H, Kojima M, Kanmatsuse K, Kangawa K (2003) Cardiovascular and hormonal effects of subcutaneous administration of ghrelin, a novel growth hormone-releasing peptide, in healthy humans. Clin Sci 105:431–435

    Article  PubMed  CAS  Google Scholar 

  • Ghelardoni S, Carnicelli V, Frascarelli S, Ronca-Testoni S, Zucchi R (2006) Ghrelin tissue distribution: comparison between gene and protein expression. J Endocrinol Invest 29:115–121

    PubMed  CAS  Google Scholar 

  • Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, Bhattacharya S, Carpenter R, Grossman AB, Korbonits M (2002) The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab 87:2988–2990

    Article  PubMed  CAS  Google Scholar 

  • Gualillo O, Lago F, Gomez-Reino J, Casanueva FF, Dieguez C (2003) Ghrelin, a widespread hormone: insights into molecular and cellular regulation of its expression and mechanism of action. FEBS Lett 552:105–109

    Article  PubMed  CAS  Google Scholar 

  • Gualillo O, Caminos J, Blanco M, Garcia-Caballero T, Kojima M, Kangawa K, Dieguez C, Casanueva F (2001) Ghrelin, a novel placental-derived hormone. Endocrinology 142:788–794

    Article  PubMed  CAS  Google Scholar 

  • Guan XM, Yu H, Palyha OC, McKee KK, Feighner SD, Sirinathsinghji DJ, Smith RG, Van der Ploeg LH, Howard AD (1997) Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Mol Brain Res 48:23–29

    Article  PubMed  CAS  Google Scholar 

  • Hattori N, Saito T, Yagyu T, Jiang BH, Kitagawa K, Inagaki C (2001) GH, GH receptor, GH secretagogue receptor, and ghrelin expression in human T cells, B cells, and neutrophils. J Clin Endocrinol Metab 86:4284–4291

    Article  PubMed  CAS  Google Scholar 

  • Heightman TD, Scott JS, Longley M, Bordas V, Dean DK, Elliott R, Hutley G, Witherington J, Abberley L, Passingham B, Berlanga M, de Los Frailes M, Wise A, Powney B, Muir A, McKay F, Butler S, Winborn K, Gardner C, Darton J, Campbell C, Sanger G (2007) Potent achiral agonists of the ghrelin (growth hormone secretagogue) receptor. Part I: Lead identification. Bioorg Med Chem Lett 17:6584–6587

    Article  PubMed  CAS  Google Scholar 

  • Hosoda H, Kojima M, Kangawa K (2006) Biological, physiological, and pharmacological aspects of ghrelin. J Pharmacol Sci 100:398–410

    Article  PubMed  CAS  Google Scholar 

  • Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsinghji DJ, Dean DC, Melillo DG, Patchett AA, Nargund R, Griffin PR, DeMartino JA, Gupta SK, Schaeffer JM, Smith RG, Van der Ploeg LH (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273:974–977

    Article  PubMed  CAS  Google Scholar 

  • Hou Z, Miao Y, Gao L, Pan H, Zhu S (2006) Ghrelin-containing neuron in cerebral cortex and hypothalamus linked with the DVC of brainstem in rat. Regul Pept 134:126–131

    Article  PubMed  CAS  Google Scholar 

  • Kojima M, Kangawa K (2005) Ghrelin: structure and function. Physiol Rev 85:495–522

    Article  PubMed  CAS  Google Scholar 

  • Kojima M, Hosoda H, Kangawa K (2001a) Purification and distribution of ghrelin: the natural endogenous ligand for the growth hormone secretagogue receptor. Horm Res 56:93–97

    Article  PubMed  CAS  Google Scholar 

  • Kojima M, Hosoda H, Matsuo H, Kangawa K (2001b) Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor. Trends Endocrinol Metab 12:118–122

    Article  PubMed  CAS  Google Scholar 

  • Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656–660

    Article  PubMed  CAS  Google Scholar 

  • Lago F, Gonzalez-Juanatey JR, Casanueva FF, Gomez-Reino J, Dieguez C, Gualillo O (2005) Ghrelin, the same peptide for different functions: player or bystander? Vitam Horm 71:405–432

    Article  PubMed  CAS  Google Scholar 

  • Lutter M, Sakata I, Osborne-Lawrence S, Rovinsky SA, Anderson JG, Jung S, Birnbaum S, Yanagisawa M, Elmquist JK, Nestler EJ, Zigman JM (2008) The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat Neurosci 11:752–753

    Article  PubMed  CAS  Google Scholar 

  • Masuda Y, Tanaka T, Inomata ON, Tanaka S, Itoh Z, Hosoda H, Kojima M, Kangawa K (2000) Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun 276:905–908

    Article  PubMed  CAS  Google Scholar 

  • Murray CD, Martin NM, Patterson M, Taylor SA, Ghatei MA, Kamm MA, Johnston C, Bloom SR, Emmanuel AV (2005) Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study. Gut 54:1693–1698

    Article  PubMed  CAS  Google Scholar 

  • Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, Matsukura S (2001) A role for ghrelin in the central regulation of feeding. Nature 409:194–198

    Article  PubMed  CAS  Google Scholar 

  • Pan LC, Carpino PA, Lefker BA, Ragan JA, Toler SM, Pettersen JC, Nettleton DO, Ng O, Pirie CM, Chidsey-Frink K, Lu B, Nickerson DF, Tess DA, Mullins MA, MacLean DB, DaSilva-Jardine PA, Thompson DD (2001) Preclinical pharmacology of CP-424, 391, an orally active pyrazolinone-piperidine growth hormone secretagogue. Endocr 14:121–132

    Article  CAS  Google Scholar 

  • Patchett AA, Nargund RP, Tata JR, Chen MH, Barakat KJ, Johnston DB, Cheng K, Chan WW, Butler B, Hickey G, Jacks T, Schleim K, Pong SS, Chuang LYP, Chen HY, Frazier E, Leung KH, Chiu SHL, Smith RG (1995) Design and biological activities of L-163, 191 (MK-0677): a potent, orally active growth hormone secretagogue. Proc Natl Acad Sci U S A 92:7001–7005

    Article  PubMed  CAS  Google Scholar 

  • Peeters TL (2005) Ghrelin: a new player in the control of gastrointestinal functions. Gut 54:1638–1649

    Article  PubMed  CAS  Google Scholar 

  • Santos M, Bastos P, Gonzaga S, Roriz JM, Baptista MJ, Nogueira-Silva C, Melo-Rocha G, Henriques-Coelho T, Roncon-Albuquerque R Jr, Leite-Moreira AF, De Krijger RR, Tibboel D, Rottier R, Correia-Pinto J (2006) Ghrelin expression in human and rat fetal lungs and the effect of ghrelin administration in nitrofen-induced congenital diaphragmatic hernia. Pediatr Res 59:531–537

    Article  PubMed  CAS  Google Scholar 

  • Schussler P, Uhr M, Ising M, Weikel JC, Schmid DA, Held K, Mathias S, Steiger A (2006) Nocturnal ghrelin, ACTH, GH and cortisol secretion after sleep deprivation in humans. Psychoneuroendocrinology 31:915–923

    Article  PubMed  CAS  Google Scholar 

  • Spooner RI, Thomson A, Hall J, Morris RG, Salter SH (1994) The Atlantis platform: a new design and further developments of Buresova's on-demand platform for the water maze. Learn Mem 1:203–211

    PubMed  CAS  Google Scholar 

  • Tanaka K, Minoura H, Isobe T, Yonaha H, Kawato H, Wang DF, Yoshida T, Kojima M, Kangawa K, Toyoda N (2003) Ghrelin is involved in the decidualization of human endometrial stromal cells. J Clin Endocrinol Metab 88:2335–2340

    Article  PubMed  CAS  Google Scholar 

  • Tschop M, Smiley DL, Heiman ML (2000) Ghrelin induces adiposity in rodents. Nature 407:908–913

    Article  PubMed  CAS  Google Scholar 

  • Volante M, Fulcheri E, Allia E, Cerrato M, Pucci A, Papotti M (2002) Ghrelin expression in fetal, infant, and adult human lung. J Histochem Cytochem 50:1013–1021

    PubMed  CAS  Google Scholar 

  • Weikel JC, Wichniak A, Ising M, Brunner H, Friess E, Held K, Mathias S, Schmid DA, Uhr M, Steiger A (2003) Ghrelin promotes slow-wave sleep in humans. Am J Physiol - Endocrinol Metabol 284:E407–E415

    CAS  Google Scholar 

  • Witherington J, Abberley L, Briggs MA, Collis K, Dean DK, Gaiba A, King NP, Kraus H, Shuker N, Steadman JG, Takle AK, Sanger G, Wadsworth G, Butler S, McKay F, Muir A, Winborn K, Heightman TD (2008) Potent achiral agonists of the growth hormone secretagogue (ghrelin) receptor. Part 2: Lead optimisation. Bioorg Med Chem Lett 18:2203–2205

    Article  PubMed  CAS  Google Scholar 

  • Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, Kennedy AR, Roberts GH, Morgan DG, Ghatei MA, Bloom SR (2000) The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 141:4325–4328

    Article  PubMed  CAS  Google Scholar 

  • Zigman JM, Jones JE, Lee CE, Saper CB, Elmquist JK (2006) Expression of ghrelin receptor mRNA in the rat and the mouse brain. J Comp Neurol 494:528–548

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Paul F Chapman from GlaxoSmithKline Centre for Cognition and Neurodegeneration, Singapore for his advice with regards to the manuscript and Simon Bate and Andrew Lloyd from the GSK Discovery Statistics Department for their advice with respect to the statistical analysis of these data.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Zeenat Atcha.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Atcha, Z., Chen, WS., Ong, A.B. et al. Cognitive enhancing effects of ghrelin receptor agonists. Psychopharmacology 206, 415–427 (2009). https://doi.org/10.1007/s00213-009-1620-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-009-1620-6

Keywords

Navigation